Tin Psychiatryrends and Psychotherapy Review Article

Exposure to during infancy and adolescence in non-human animals and sensitization to abuse of psychostimulants later in life: a systematic review

Exposição a metilfenidato na infância e adolescência em modelos não humanos e sensibilidade ao abuso de drogas psicoestimulantes na vida adulta: revisão sistemática

Juliana Jaboinski,1,2 João Carlos Centurion Cabral,1 Renan Campos,2,3 Daniela Marti Barros2

Abstract Resumo

Introduction: Attention deficit hyperactivity disorder (ADHD) is Introdução: O transtorno de déficit de atenção e hiperatividade a neuropsychiatric that has an important prevalence (TDAH) é uma patologia neuropsiquiátrica de difícil diagnóstico e de among young people and is difficult to diagnose. It is usually tre- relevante prevalência entre pessoas jovens. É comumente tratada ated with methylphenidate, a psychostimulant with a mechanism com metilfenidato, uma substância psicoestimulante com meca- of action similar to that of cocaine. Previous studies show that nismo de ação similar ao da cocaína. Estudos prévios demonstram repeated use of psychostimulants during childhood or adolescence que o uso contínuo de fármacos estimulantes na infância ou ado- may sensitize subjects, making them more prone to later abuse lescência pode sensibilizar o sujeito para o subsequente abuso de of psychostimulant drugs such as cocaine and methamphetamine. drogas psicoestimulantes, como cocaína e metanfetamina. Objective: To review experimental studies in non-human mo- Objetivo: Revisar estudos experimentais em modelos não hu- dels (rodents and monkeys) treated with methylphenidate du- manos (roedores e macacos) tratados com metilfenidato na in- ring infancy or adolescence and tested for reinforcing effects on fância ou na adolescência e testados para os efeitos reforçadores psychostimulant drugs in adulthood. de drogas psicoestimulantes na vida adulta. Method: Systematic collection of data was performed on four Método: A coleta sistemática dos dados foi realizada em quatro databases (Web of Knowledge, PsycARTICLE, PubMed and SciE- bases de dados (Web of Knowledge, PsycARTICLE, PubMed e LO). The initial search identified 202 articles published from SciELO). Na busca inicial, 202 artigos publicados entre 2009 e 2009 to 2014, which were screened for eligibility. Seven articles 2014 foram triados. Destes, sete preencheram os critérios de met the inclusion criteria and were reviewed in this study. inclusão e foram revisados neste estudo. Results: The findings indicate that early exposure to methylphe- Resultados: Os dados indicam um efeito da pré-exposição ao nidate has an effect on an ADHD animal model, specifically, on metilfenidato sobre o TDAH em animais adolescentes da linha- spontaneously hypertensive strain rats, especially those tested gem do rato espontaneamente hipertensivo (spontaneously using the self-administration paradigm. hypertensive strain, SHR). Esse efeito foi encontrado, sobretudo, Conclusion: Future studies should prioritize the spontaneously nos estudos que utilizaram o paradigma de autoadministração. hypertensive rat strain – an animal model of ADHD. Experimen- Conclusão: Estudos futuros devem priorizar a linhagem dos SHR – tal designs comparing different behavioral paradigms and modes modelo animal do TDAH. Delineamentos que comparem diferentes of administration using this strain could lead to improved un- paradigmas comportamentais e formas de administração utilizando derstanding of the effects of exposure to methylphenidate during essa linhagem podem prover uma melhor compreensão do efeito childhood and adolescence. da exposição ao metilfenidato na infância e adolescência. Keywords: Methylphenidate, attention deficit hyperactivity di- Descritores: Metilfenidato, transtorno de déficit de atenção e hipe- sorder, animal models, analeptic drugs, drug abuse. ratividade, modelos animais, drogas analépticas, abuso de drogas.

1 Institute of Psychology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. 2 Institute of Biological Sciences, Universidade Federal do Rio Grande (FURG), Rio Grande, RS, Brazil. 3 Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, Université de Bordeaux, Bordeaux, France. Financial support: none. Submitted Dec 18 2014, accepted for publication Apr 25 2015. No conflicts of interest declared concerning the publication of this article. Suggested citation: Jaboinski J, Cabral JC, Campos R, Barros DM. Exposure to methylphenidate during infancy and adolescence in non-human animals and sensitization to abuse of psychostimulants later in life: a systematic review. Trends Psychother. 2015;37(3):107-117. http://dx.doi.org/10.1590/2237- 6089-2014-0060

APRS Trends Psychiatry Psychother. 2015;37(3) – 107-117 Methylphenidate exposure and abuse - Jaboinski et al.

Introduction The pharmacological action of MPH is ascribed to blockage of dopamine (DA) and noradrenaline (NA) Stimulant drugs have been used to treat attention reuptake within the prefrontal cortex, thereby increasing deficit hyperactivity disorder (ADHD) for more than 70 the levels of both neurotransmitters in this region and years. This disorder is usually diagnosed in children and enhancing the functions for which they are responsible teenagers and may persist through adulthood.1 (attention, inhibitory control and working memory).1 Relevant concerns have been raised in recent decades Interestingly, cocaine also causes increased availability regarding the impact of chronic use of psychostimulants of DA, in particular in the dopaminergic mesolimbic such as methylphenidate (MPH) during brain development. pathway, which is known as the reward pathway in One pertinent point raised is the hypothesis that use of the brain. A large body of evidence suggests that this MPH during childhood and adolescence may sensitize action within the reward circuitry underlies the addictive the developing brain, eliciting susceptibility to drug properties of cocaine.6,8-10 Thus, both ADHD patients abuse (especially to psychostimulants) in adulthood.2 and people addicted to cocaine are likely to have a Considering the widespread use of this drug, studies that common neuronal need for dopaminergic stimulation. aim to investigate its potential impact on the development Nonetheless, the direction of this relationship in terms of the brain are warranted, especially when they concern of whether MPH sensitizes the subject’s brain for potential adverse consequences such as drug addiction. subsequent use of psychostimulants or constitutes a Attention deficit hyperactivity disorder is a protective tool remains a mystery. neuropsychiatric pathology with an important prevalence On one hand, some studies have assessed utilization among young people and its rate of diagnosis has of MPH as a pharmacological tool for treatment of increased by 41% over the last 10 years, with a cocaine11,12 and methamphetamine (MET)13 addictions significant increase among male adolescents aged 14 and there seems to be a consensus in the literature that to 17.3 Diagnosis of this disorder is based on persistent MPH is not a viable method for this purpose. On the other dysfunctional levels of attention, impulsivity and motor hand, other studies have been conducted to evaluate the activity (hyperactivity).4 To date there are no known capacity of MPH to elicit subsequent drug abuse. In one biological markers or laboratory tests that can confirm study, Kollins et al.14 reviewed 60 studies of humans with its presence and so the disorder is mainly identified and without ADHD diagnoses and of several animal models through observation of behavioral features.4 (e.g., rat, baboon, monkey, dog and squirrel). The aim According to the fifth edition of the Diagnostic and of that study was to evaluate the pharmacological and Statistical Manual of Mental Disorders (DSM-5),5 ADHD behavioral profiles of MPH, discussing implications for its is characterized by 18 symptoms, nine of which are potential abuse, while making a comparison with other related to inattention traits, six to hyperactivity traits psychostimulants such as cocaine and D-. and three to impulsivity traits. The cutoff for diagnosis is Of the 60 studies reviewed, the authors asserted that 48 six traits, i.e. the number of symptoms above which the demonstrated that MPH acted in a similar way to cocaine subject is diagnosed with ADHD is six inattention traits and D-amphetamine, exhibiting reinforcing effects and and/or six hyperactivity-impulsivity traits. The cutoff for similar subjective effects in humans, assessed using self- adults is five traits. report scales. In contrast, Wilens et al.15 reviewed six The pathophysiology of ADHD is believed to be related studies using a meta-analysis approach and suggested to an abnormality within the catecholaminergic signaling that treatment with during adolescence system involving release of dopamine (DA) in areas was not associated with an increased predisposition to such as the frontal lobe and those involving the limbic abuse of a range of types of drug – including alcohol system.6 One theory postulated to explain the etiology and psychostimulants. Interestingly, that study compiled of ADHD is a fronto-striatal dopaminergic hypofunction. results that ascribed a protective component to the use Because the frontal lobe, mainly the prefrontal of stimulant medication for ADHD. Further blurring the cortex, is responsible for attentional and regulatory subject, recent work has found no relationship between processes (inhibitory control, impulsivity), and the chronic MPH use during childhood and adolescence and nigrostriatal pathway is responsible for motor activities drug abuse in adult life.16 (hyperactivity), the clinical features of ADHD correlate Studies using animal models aim to understand the to the areas involved. However, the neurobiology of this effects of drugs on the physiology of the brain and enable disorder is likely to involve more than dopaminergic controlled behavioral evaluation and investigation of the hypofunction, since not all patients respond well to the biological mechanisms underlying such processes. In the standard medication, MPH, and not all psychostimulants case of drug addiction, several paradigms have been appear to be effective for treatment.6,7 widely used to mimic addiction-related processes in non-

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human animal models. Some of them appear recurrently the results suggest that pretreatment with MPH could throughout the studies included in this review and are increase vulnerability to cocaine abuse later in life, as therefore worth mentioning. demonstrated by cross-sensitization between these In the conditioned place preference (CPP) paradigm, two stimulants, and may also enhance these animals’ animals are administered a drug prior to being placed in vulnerability to the reinforcing effects of cocaine, as one environment/context. In another session they are observed through increased cocaine self-administration. administered with a neutral substance (a vehicle injection) Another study using a non-human primate model (Rhesus before being placed in an alternative environment. monkeys) was designed to compare the reinforcing Following several pairing sessions, the animals are properties of Atomoxetine, a non-stimulant medication allowed to move freely between the two environments, for ADHD, with the effects of two other drugs, MPH and while in a drug-free state, and the amount of time spent desipramine. In order to achieve this, the animals were in the drug-associated context is taken as an index of initially sensitized with cocaine and afterwards were preference for the drug.17-19 Another recurrent behavioral given the opportunity to self-administer atomoxetine, paradigm is used to assess aversive properties of drugs. desipramine or MPH. The results indicated that MPH, The conditioned taste aversion (CTA) task evaluates similarly to cocaine and conversely to Atomoxetine animals’ tendency to reduce consumption of a usually and Desipramine, functioned as a positive reinforcer.29 preferred substance (e.g., sucrose, saccharin, water). These data support previous reports using rodents as After several pairings of this substance with a specific models.28 On the other hand, a more recent publication drug, a reliable reduction in fluid intake is produced, thus demonstrated that repeated treatment with intragastric conveying a learned association between the aversive MPH did not induce behavioral sensitization in adolescent effects of the drug and the taste of the substance.20 rats. Additionally, cross-sensitization was also not The self-administration model has been successfully observed when the animals underwent early treatment used to measure psychostimulant reinforcement in with MPH and were later challenged with nicotine during non-human animal models.21-23 In this model, animals adolescence or adulthood.30 are trained to perform an action in order to receive an Finally, this brief review indicates that some questions infusion of a drug. In this kind of experiment, various regarding the effects of early administration of MPH different manipulations can be performed to examine still remain to be answered: does early administration their effects on self-administration. One useful feature induce sensitization or lead to enhanced proneness to of the self-administration model is its capacity to mimic later psychostimulant abuse? Approaching this complex real-life drug-taking in humans.24 subject within a neuropsychopharmacological puzzle, Finally, one further recurrent approach is an this review aims to cover a modest proportion of this assessment of locomotor sensitization/cross- field. Therefore, we performed a systematic review of sensitization, based on a phenomenon by which locomotor the effects of exposure to MPH during childhood and activity is enhanced following a drug challenge using a adolescence on abuse of psychostimulant drugs later in dose to which the animal has repeatedly been exposed life. In view of the multiplicity of variables to be analyzed, previously. In cross-sensitization, animals repeatedly as well as the difficulty of comparing results obtained treated with one stimulant display greater locomotor from studies with humans, this review focuses on studies activity when later exposed to another stimulant.25 that utilized non-human animal models (rodents and Locomotor sensitization is considered a behavioral model monkeys). It is believed that the data they produce allow of drug induced neuronal plasticity,26 being paralleled by for a more concise and productive discussion because neuroadaptations underlain by changes in molecular of the possibility of greater control of variables in such signaling cascades.27 models. However, even using this kind of experimental evaluation, studies of MPH with humans and with non- human animal models have reported complex and Materials and methods variable results. For instance, a study published by Brandon et Systematic collection of data was performed in June al.28 using adolescent male Sprague-Dawley (SD) rats 2014 using the following electronic databases: Web of demonstrated that MPH may have a sensitizing effect Knowledge (ISI), PsycARTICLE (APA), PubMed (MEDLINE) towards use of cocaine in adulthood.13 Animals exhibited and SciELO (Scielo.org). Articles published between locomotor cross-sensitization when initially exposed to 2009 and 2014 were sampled using the following search MPH and afterwards to cocaine. Pretreatment with MPH strategy: (((Methylphenidate [Title]) OR (Ritalin [Title])) also increased self-administration of cocaine.28 As such, AND ((Animal [Title/Abstract]) OR (mice [Title/Abstract])

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OR (rat [Title/Abstract]) OR (rodent [Title/Abstract]) OR variable; b) study design – studies that did not use an (primate [Title/Abstract])) AND ((Self-administration experimental design; and c) accessibility – articles that [Title/Abstract]) OR (“substance dependence” [Title/ were not available for online access. Abstract]) OR (“substance use” [Title/Abstract]) OR At the end of this process, seven articles were selected (“long term effects” [Title/Abstract])) AND ((Drugs for review (Figure 1). The rate of agreement between the [Title/Abstract]) OR (cocaine [Title/Abstract]) OR reviewers was 96.3%. In cases of discrepancies between (nicotine [Title/Abstract]) OR (addiction [Title/Abstract]) the two reviewers’ evaluations, a third researcher was OR (abuse [Title/Abstract]))). requested to participate. The initial searches located a total of 202 publications. The articles reviewed were organized by author, These underwent a screening process to assess their publication year, sample size, animal model (including adequacy based on inclusion and exclusion criteria and strain), MPH dose and route of administration, period to evaluate the methodology of the studies. This process of development during which the exposure to MPH was was carried out by two independent reviewers previously carried out, behavioral task and main results (Table 1). It trained for the task. The following items were selected as is important to mention that the periods of development inclusion criteria: a) aim of the study – articles designed to that were included in this review were from the beginning investigate the long-term effects of methylphenidate on of weaning to late adolescence. Weaning is a transition recreational drug use; b) independent variable – articles between two modes of feeding, and is a progressive and in which at least one of the independent variables is developmental process unique to mammalian young. use of methylphenidate; c) type of publication – articles Rats mature rapidly during infancy and become sexually published in peer-reviewed scientific journals; d) period mature at about 6 weeks of age.31,32 Indeed, the average of publication – articles published from 2009 to 2014; weaning age for rats is approximately 3 weeks and the and e) language – articles published in English, Spanish late adolescence is approximately up to postnatal day 42, or Portuguese. Articles that were not relevant were which is the period considered in this review. Non-human then excluded by application of the following criteria: primates have an extended period of adolescence,33 a) dependent variable – studies that did not contain so the late adolescence period for primates (rhesus the use of at least one stimulant drug as a dependent monkeys) was considered as up to 4.5 years.34

Identified articles Identified articles: Identified articles: Identified articles: SCOPUS PubMed Web Of Science PsycInfo (n = 76) (n = 57) (n = 26) (n = 43)

Total number of articles identified (n = 202) Duplicate articles (74)

Total number of Year of publication (78) articles identified (n = 128) Language (3) Publications that did not meet the inclusion criteria Objtective of study (31) (116) Total number of articles identified Independent variable (n = 12) (4)

Exclusion criteria Dependent variable (3) (5)

Study design (1) Total number of articles identified Accessibility of article (n = 7) (1)

Figure 1 - Article selection process

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Table 1 - Studies of early exposure to methylphenidate and risk of later stimulant drug use in animal models

Study n (CG-EG) Animals/ MPH dose/ Beginning Dependent Main results strains administration of exposure: variables route development period Jordan et al.3 10-7/10-10/9-7 SHR vs. WKY Clinical: 1.5 mg/ Adolescence (25 Cocaine SA (0.3 SHR (↑ Cocaine and WIS rats (♂) kg/oral route days) mg/kg) SA) WKY and WIS (NS) Gill et al.35 8/8 Rhesus monkeys Clinical: 20-40 Adolescence Cocaine SA D2/D3 receptor (♂) mg/oral route (40.5-38 months) (0.001 to 0.1 availability (NS) mg/kg) DAT availability Morphometric (NS) measures Cocaine SA (NS) PET imaging: D2/ D3 receptors and DAT Wetzell & Riley 42/42 Sprague Dawley Clinical: 2 mg/kg Adolescence (25 CTA NS (Exp. 1)36 rats (♂) / Intraperitoneal days) route Wetzell & Riley 24/24 Sprague Dawley Non-clinical: Adolescence (25 CTA NS (Exp. 2)36 rats (♂) 10 mg/kg / days) Intraperitoneal route Peña et al.37 _ SHR X WIS rats Clinical: 1.25 Adolescence (21 CPP (MPH) MPH as a (♂) mg/kg days) reinforcer: Non-Clinical: 5 WIS (significant mg/kg when compared 25 mg/kg/ with CG) intraperitoneal SHR (NS when route compared with CG) Harvey et al.21 ±6-8 per group SHR X WKY and Clinical: 1.5 mg/ Adolescence (25 Cocaine SA MPH-treated WIS rats (♂) kg/oral route days) (0.003 to 1 mg/ SHR exhibited: kg) faster cocaine SA; Functioning of upward shift in DAT the cocaine dose- response function; ↓ DAT in the PFC Crawford et ±6-9 per group Sprague Dawley Clinical: 0.2 mg/ Childhood (11 Cocaine SA MPH (↑ Cocaine al.22 rats (♀/♂) kg days) (0.25/0.75 mg/ SA (♂ only)) Non-Clinical: kg/infus.) MPH X CPP (NS) 5 mg/kg/ CPP intraperitoneal route Griggs et al.23 8-10 per group Sprague Dawley Clinical: 1.5 mg/ Adolescence (37 Cocaine SA (1 Intermittent MPH rats (♂) kg days) mg/kg/infus.) administration: 3 mg/kg/ hyperactivity in subcutaneous several measures route and ↑ sensitivity to the reinforcing effects of cocaine; continuous MPH administration: hypoactivity and cocaine SA (NS)

♂ = male; ♀ = female; ↑ = increase; ↓ = decrease; CG = control group; CPP = conditioned place preference; CTA = conditioned taste aversion; DAT = dopamine transporter; EG = experimental group; Exp. = experiment; infus. = infusion; MPH = methylphenidate; NS = not significant; PFC = prefrontal cortex; SA = self- administration; SHR = spontaneously hypertensive rat; WIS = Wistar rat; WKY = Wistar-Kyoto rat.

Results to MPH during childhood/adolescence on subsequent use of psychostimulants. In contrast, two studies did observe In total, seven studies that met all of the inclusion such effects. Finally, the three remaining studies compared criteria defined for this systematic review were included. different methodological aspects such as animal strains, Two of these studies did not detect any effect from exposure behavioral tasks or routes of drug administration.

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Studies reporting no effect of early results cover three important aspects regarding the use exposure to MPH on adult life of MPH during infancy and adolescence: body growth, development of the dopaminergic system and future Wetzell & Riley36 examined the effects of adolescent vulnerability to drug abuse. As a result, the authors exposure to MPH on the aversive properties of cocaine in concluded that their observations support the hypothesis adulthood using the CTA procedure. In order to address that use of MPH for treatment of ADHD during childhood this issue, male SD rats were intraperitoneally (ip) does not lead to long-term adverse developmental or administered with either a therapeutic (2 mg/kg, two daily to neurobiological or behavioral consequences over the sessions) or a high dose (10 mg/kg one daily session) of course of treatment or later in adolescence. MPH for 15 consecutive days during adolescence, and Several methodological features of this study should then tested in the CTA task with cocaine. It is important be highlighted. The use of non-human primates is to note that the dose of MPH regarded as therapeutic advantageous since it presents a higher similarity, in was based on its equivalence to therapeutic doses used comparison to humans, in terms of neurophysiological in adolescent humans.38 The results showed that early processes, developmental windows (infancy and exposure to MPH does not alter the aversive properties adolescence) and the hormonal and maturational of cocaine in adulthood. Thus, the authors argue that changes and complexity of social and cognitive processes the increases in cocaine self-administration during that accompany these periods. Also, the choice of the adulthood following chronic adolescent exposure to MPH extended release formulation of MPH has an important are unlikely to be founded on changes in the aversive translational aspect, since this kind of formulation properties to cocaine, as evaluated by CTA, but rather prolongs MPH release, maintaining plasma concentrations could only be related to the alterations in the reinforcing for a longer period, and is therefore more clinically properties of cocaine promoted by previous MPH relevant.46 Furthermore, the authors suggest that the exposure. It is relevant to observe that since the neural non-involvement of MPH in body growth corroborates mechanisms that mediate CTA39 are distinguishable from recent findings demonstrating that while some those that mediate reward,40 both constructs can vary alterations in measurements such as weight and height independently.41,42 may be observed, these effects tend to be attenuated The study published by Gill et al.35 also failed to detect over time and do not impact adult life.47,48 Finally, there effects in adulthood following 1 year of MPH treatment in seems to be an inconsistency among preclinical studies 16 male Rhesus monkeys (approximately 37-54 months showing no differences in rates of acquisition of cocaine old, corresponding to a period between 9 and 13 years of reinforcement after chronic treatment with MPH.21,22 age in humans),43 using an extended release formulation Gill et al.35 explain this inconsistency by highlighting of MPH at doses targeted to be within a clinically the differences in the dose of cocaine initially delivered relevant range. The first objective of this study was to to the animals in the self-administration paradigm. In characterize the changes in dopamine transporter (DAT) this study, Gill et al.35 provided the animals with lower and DA receptor function through positron emission initial doses of cocaine, which were below reinforcing tomography scans. Availability of these proteins is thresholds. It therefore seems logical that higher initial regularly associated with vulnerability to abuse of doses would result in a more pronounced difference psychostimulants. The second objective was to evaluate between groups. subjects’ morphometric measures, e.g. weight, crown- rump length, abdominal and chest circumference. The Studies reporting effects of early reason for conducting morphometric assessments lies in exposure to MPH on adult life the fact that some reports have argued one side effect of MPH use during development is growth suppression.44,45 In contrast to the two studies described above, two Finally, the third objective was to evaluate vulnerability other studies did find effects in adulthood following to the reinforcing effects of cocaine after pre-exposure to exposure to MPH during infancy/adolescence.3,21 MPH, using the self-administration paradigm. Overall, no Both works utilized cocaine self-administration after differences were found between groups in the availability treatment with MPH and compared males of three rodent of D2/D3 or DATs following exposure to MPH during late strains, namely Wistar (WIS), Wistar Kyoto (WKY) and infancy. There were also no differences in morphometric the spontaneously hypertensive rat (SHR), the last of measurements among animals that had been pre- which is widely used as an animal genetic model for exposed to MPH. Additionally, no alterations were ADHD because it exhibits behavioral correlates with this observed in the reinforcing properties of cocaine after disorder.49,50 However, each study has some relevant chronic administration of MPH. Taken together, these peculiarities. For instance, Harvey et al.21 assessed DAT

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functionality in specific brain areas (the prefrontal cortex exposure with those of MET, another psychostimulant and striatum), while Jordan et al.3 also administered drug that has a well-known highly addictive potential. One atomoxetine, with the intention of comparing the of the hypotheses was that early exposure to MET could effects of exposure to both drugs during adolescence increase its own reinforcing properties later in adulthood on cocaine self-administration during adulthood. Both in both strains, although with a more pronounced studies used the same dose of MPH (1.5 mg/kg) and the effect on the SHR strain. It was also hypothesized same route of administration (oral), finding an increase that early exposure to MPH would increase its own in the reinforcing properties of cocaine within the SHR reinforcing properties later in adulthood, particularly in group. These results suggest that this model exhibits the SHR strain, which is regarded as an ADHD model. different effects of adolescent ADHD medications on Furthermore, the authors also intended to compare the cocaine intake during adulthood, since it seems to have strains (WIS and SHR), since most preclinical studies a greater motivation for cocaine reinforcement after were conducted with non-ADHD animals, questioning adolescent methylphenidate treatment than do WKY whether the responses of non-ADHD animals could also or WIS rats. The mechanisms underlying this potential be generalized to a “pathological” state. greater motivation remain elusive. Although the study The results show that both WIS and SHR rats, carried out by Harvey et al.,17 showed effects on the SHR when repeatedly treated with MET, exhibited CPP to strain caused by administration of MPH, no significant this drug in adulthood. However, in contrast with what difference was observed in the functionality of DATs the authors had hypothesized, in the SHR strain early in the areas assessed. The hypothesis that DAT could MPH treatment did not produce CPP when the animals be involved in this process, since both SHR and ADHD were posteriorly exposed to MPH. Interestingly, WIS rats patients have a disturbance in the regulation of DAT exhibited a greater response to the rewarding effects of translation (Sagvolden et al.51), was discarded by Harvey MPH than SHR did. The authors suggested that this could et al.,21 because the results obtained in their study indicate that ‘normal’ individuals are more vulnerable to suggest that the enhanced cocaine self-administration in MPH abuse or dependence. With regard to the animals methylphenidate-treated SHRs is not related to potential from the SHR strain, the authors pointed out that other striatal DAT density changes. studies have also reported results that do not confirm Interestingly, Jordan et al.3 did not observe the the current position in the literature on this matter. For same effect of exposure to MPH in the SHR strain when instance, Yang et al.,52,53 designed an experiment in atomoxetine was used. The SHR animals treated with MPH which three different strains (WKY, SD and SHR) were and during adolescence responded differently in terms of subjected to chronic administration of a moderate dose cocaine self-administration during adulthood to animals of MPH (2.5 mg/kg, ip, for 6 days). The MPH treatment treated with atomoxetine, with MPH increasing the elicited locomotor sensitization in WKY and SD rats, but reinforcing properties of cocaine, whereas atomoxetine not in SHR. However, as locomotor sensitization and did not. These data are in accordance with the results of CPP do not assess the same elements of the reinforcing previous studies using non-human primates.29 properties of drugs, comparisons between behavioral paradigms should be interpreted with caution. Finally, Studies comparing the effects of different the authors suggest that MPH may have a better safety methodological aspects of early exposure profile for treatment of ADHD, compared with MET and/ to MPH on adult life or amphetamine. Studies employing behavioral paradigms have Finally, the three remaining studies organized in this observed differing results that vary with different tasks. last section share a common feature: they compared For instance, increases in the rewarding value of cocaine methodological aspects. In these studies different were observed in rodents submitted to cocaine self- strains, behavioral paradigms and MPH administration administration,3,21 whereas animals (especially from the protocols are compared. SHR strain) tested with the CPP task exhibit decreased In the first study, Peña et 37 al. administered three rewarding effects.37 doses of MPH (1.25 mg/kg, 5 mg/kg, 20 mg/kg, ip) and To address this question, Crawford et al.22 compared two doses of MET (1.25 mg/kg, 5 mg/kg, ip) to rodents two different behavioral paradigms with the intention of of two different strains (WIS and SHR) before evaluating revealing the effects of early exposure to MPH. This study the same drugs in the CPP task. The objectives of this also investigates sex differences using male and female study were to evaluate the impact of exposure to MPH rodents of the SD strain. The animals were exposed to during adolescence on its own rewarding effects later MPH (0.2 mg/kg or 5 mg/kg, ip) during infancy and, in adulthood and to compare the effects of early MPH after reaching adulthood, were submitted to cocaine self-

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administration (0.25 or 0.75 mg/kg, intravenous) and to intervention on subsequent use of psychostimulants the CPP paradigm with cocaine (0.1 or 20 mg/kg, ip). during adulthood. The review’s findings show that the Effects were only observed among male subjects that had results are divergent, according to the methodological been exposed to MPH and these effects were only observed features of each study. Overall, effects of early exposure in relation to cocaine self-administration. Females used in to MPH were observed in studies that utilized an ADHD this study did not exhibit effects of exposure to MPH in animal model: SHR rats. This is suggested by the idea that any of the tasks. The authors observed that male rats their exposure to MPH during infancy and adolescence exposed to MPH during infancy were more susceptible to underlies the different behavior displayed by the SHR the reinforcing properties of cocaine (accessed through animals towards later exposure to psychostimulants. self-administration) but were not sensitive to the cues Nevertheless, some methodological aspects ought to be related to cocaine, as observed through the CPP task. discussed, since a clearer understanding of these results The results reported by this study seem to suggest is warranted. that observation of possible different reinforcing The first feature that should be highlighted is the properties of cocaine following MPH administration range of species and strains utilized in the studies may vary depending on the characteristics of the reviewed. Three of the seven studies performed behavioral paradigm used. Regarding sex differences, it experiments using the SD strain and only one of these23 is relevant to observe that few studies include females used females in addition to males. Three other studies in their assessments of early exposure to MPH. However, compared SHR, Wistar and Wistar Kyoto strains.3,21,22 according to this study published by Crawford et al.22 Two of them observed effects from early exposure to females seem to display different effects following MPH in the SHR strain.3,21 These results indicate that such exposure when compared to male animals in the development of a model that better mimics this disorder same period of the development. This difference may is warranted. Although a number of studies compared also be reflected in the subsequent predisposition to several different strains, there are still many studies cocaine abuse. It is possible that hormonal particularities comparing non-ADHD strains, which may not accurately might underlie these differences, since estrogen has a represent the features of the disorder and the true effects neuroprotective role against some neurotoxic agents.54,55 of such exposure on individuals who have the disorder. Finally, Griggs et al.23 also reported divergent results One of the studies utilized Rhesus monkeys, a species regarding exposure to MPH during infancy. In their work, that can provide a wealth of information due to the male SD rodents were evaluated between the beginning considerable similarity of its developmental processes and end of adolescence. The animals were exposed to to those of humans. This study did not observe effects MPH for a period of four weeks. Two drug administration from early exposure to MPH nor did it detect alterations protocols were used, continuous (1.6 or 3.2 mg/kg/ to the availability of DAT or to dopaminergic D2 and D3 day via osmotic minipump) and intermittent (0.8 or receptors. One explanation for the lack of an observed 1.6 mg/kg, subcutaneously, twice daily). After drug effect on this species is founded on the same rationale as administration, the rats were submitted to locomotor the explanation related to rodents, i.e. that this animal activity tests and the self-administration protocol. The is not regarded as an ADHD model. Notwithstanding, effects of exposure to MPH were only observed in subjects Wee & Woolverton29 did demonstrate that MPH elicited that received the drug according to the intermittent reinforcing effects in Rhesus monkeys, which was administration protocol. Animals that received two daily corroborated by results reported by Lile et al.,56 with the doses of MPH, rather than receiving it continuously, were same animal model. Taken together, these results show more sensitive to the reinforcing properties of cocaine. that interpretation of the effects of MPH on non-human The authors argue that the results convey enough primates demands caution, taking into account the lack evidence to state that sustained-release formulations of consensus in the literature and the methodological are less likely to elicit the risk of subsequent substance diversity/limitations of the studies (e.g. low numbers of abuse. This hypothesis reinforces the results obtained individuals per group). Still, considering the similarities by Gill et al.35 in their study with non-human primates. of this model when compared to humans, as mentioned above, the results obtained by these studies are of great translational relevance. Discussion Furthermore, it is worth noting that the study conducted by Peña et al.,37 which compared the SHR This review describes the main results observed after and Wistar strains, did not find any effect of early exposure of non-human animal models to MPH during exposure to MPH in the ADHD model strain, although infancy and adolescence, including the impact of this the task carried out was not the same as in studies that

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did find positive effects. Unlike the two other studies, only two considering sustained-release pharmacokinetics which utilized direct drug administration, Peña et al.37 and bioavailability of MPH (Griggs et al.23 and Yang et used the CPP task, which indirectly assesses sensitivity al.35). This, to a certain extent, provides more clinically to use of psychostimulants and consists of a place-drug meaningful results. These data are also relevant with association. As such, interpretation of these data requires respect to the inference of behavioral effects of MPH, caution, since the task aims to evaluate the associative which are highly correlated with its pharmacokinetics. rather than the directly rewarding aspects of cocaine. For instance, immediate release formulations have Another important methodological question that is greater subjective effects, if compared with sustained- worth exploring is the dose of MPH used in the studies release formulations.14 It is noteworthy that, unlike the included in this review. In general, they used doses that higher doses, repeated administration of doses that are similar to those administered in the corresponding attempt to approximate the clinical pattern of MPH during developmental period (infancy and adolescence). Some adolescence and into early adulthood did not lead to the studies also tested higher doses for the purposes of developmental alterations and neurochemical effects comparison. The use of a clinically relevant dose is crucial typically associated with psychomotor stimulants.38 to studies’ ecological validity, since the aim is not only Furthermore, the three behavioral tasks utilized in to assess the impact of recreational drug use, but also the studies included in this review also raise questions to evaluate the standard pharmacological treatment for relating to the results reported. Four of the seven ADHD. Two studies also used two other doses, one lower studies employed self-administration,3,21,23,35 while one and one higher than the clinical standard.22,36 These studies compared the performance of subjects in terms of self- reported effects on CPP and self-administration tasks from administration with performance in the CPP task.22 Two early exposure to MPH at these doses. The ecological other studies utilized either CTA or CPP tasks.36,37 The validity of this intervention is, however, debatable, because results seem to be consistent throughout the different the doses administered are not commonly used. tasks, to the extent that experimental designs using self- Additionally, the different infusion protocols used administration in rodents demonstrate effects of early by Griggs et al.23 are worthy of note. In this study, exposure to MPH, while associative tasks, such as CPP the authors compared the effects of intermittent vs. and CTA, also seem to show effects of early exposure, continuous administration of MPH. They investigated but the effects observed were more subtle. the impact of different pharmacokinetic behaviors, since For instance, the self-administration training sustained-release formulations seem to enhance patient represents an instrumental form of conditioning in which compliance and appear to exert a more limited abuse the animal actively administers the drug, because it profile, thus being more difficult to divert for abusive establishes the pairing between the lever press and use. The results showed that continuous treatment with delivery of the outcome. This allows for assessment of MPH during adolescence caused rats to self-administer the rewarding properties of drugs in a condition of active less cocaine compared with intermittent administration. consumption. In contrast, CPP evaluates the motivational Their data therefore suggest that the protocol and dose properties of a specific drug. Furthermore, animals’ are relevant issues to address. avoidance of the compartment associated with the drug The route of administration may also have important and their preference for staying in the compartment paired implications for the pharmacokinetics of MPH that can with the vehicle suggests aversive rather than reinforcing profoundly influence the behavioral and neurobiological properties of the drug.58 Similar features are observed consequences associated with exposure to this class in the CTA task, which is based on the fact that animals of drugs.38 Clinically, MPH is most commonly available associate specific interoceptive states (triggered by the and administered in relatively low doses and typically drug in this case) with a specific taste. Thus, depending on involves oral administration.57 Although animal model the discriminative properties of the drug, the subject may studies are increasingly mimicking the therapeutic dose (or may not) refrain from ingesting the liquid, suggesting used in humans, a large number of studies over recent an association with the psychoactive effect of the drug. It decades have been conducted using higher doses and is also possible to evaluate an avoidance pattern with this intraperitoneal administration, which leads to a peak task, implying that the drug elicits aversive properties. plasma drug concentration that exceeds that of clinically Therefore, it is possible to interpret the results of the relevant administration of MPH.38 studies on the basis of the logic underlying the tasks. However, all of the studies reviewed took into account As previously mentioned, most of the studies that found at least one therapeutic dose of MPH, and more than effects of early exposure to MPH used self-administration half of these studies were designed to mimic the route protocols, hence, MPH may enhance the reinforcing of administration typically used in clinical settings, with properties of other psychostimulant drugs, in particular,

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cocaine. As for the other behavioral tasks utilized, they not associated with either a decrease or an increase in may not be suitable for revealing the effects of early proneness to later drug abuse. However, that study only exposure to clinically relevant doses of MPH within the assessed children, not adolescents, and this aspect may ADHD strain. This is supported by the study by Peña be relevant because the stage of development during et al.,37 which used CPP to compare the effect of early which the subject is exposed to MPH appears to be a exposure to MPH on two strains (WIS and SHR). The determining factor for prognosis of the disorder. results only revealed effects on the WIS rats and not on According to Humphreys, Eng & Lee,16 utilization the SHR strain. The authors suggested that these results of MPH during adolescence may sensitize and thus may be linked to the vulnerability of the non-ADHD brain, predispose the subject to later use of psychostimulant because the WIS strain was the only strain displaying such drugs, because important neural changes take place effects. Considering these contrasting results, studies within the dopaminergic circuitry of the prefrontal with diverse designs are needed to clarify the relationship cortex during this stage of development. Therefore, between early exposure to MPH and performance in pharmacological interventions interacting with these different tasks with regard to the strains utilized. pathways may alter the perception of the reinforcing In general, the data compiled from the studies in this properties of psychostimulants later in life. review suggest that exposure to MPH during infancy or Finally, it is believed that further studies with both adolescence may explain proneness to cocaine abuse, animals and humans are warranted to clarify the real particularly in SHR rats, which constitute an animal impact of the use of psychostimulants, in particular model for ADHD. However, the diversity of strains MPH, on the developing brain, especially concerning the used in the studies and the variety of tasks performed consumption of drugs of abuse. suggest a need for caution when evaluating the results. It is noteworthy that only one study assessed females and although ADHD does predominantly affect males, References tests with females are nevertheless warranted if a better 1. Pardey MC, Kumar NN, Goodchild AK, Clemens KJ, Homewood J, understanding of this disorder is to be achieved. Cornish JL. Long-term effects of chronic oral Ritalin administration Furthermore, only one of the studies used a species on cognitive and neural development in adolescent wistar kyoto rats. Brain Sci. 2012;2:375-404. other than rats (Rhesus monkeys), and although this 2. Andersen SL. Stimulants and the developing brain. Trends species may offer useful information for a potential Pharmacol Sci. 2005;26:237-43. 3. 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